The construction of nitrogen heterocycles is vital for the synthesis of biologically important agents. This grant concerns the development of several new methods for lactam synthesis using ring-expansion chemistry and their application to the preparation of natural products and a class of peptidomimetics. The intramolecular reaction of alkyl azides with ketones under protic or Lewis acid promoting (the intramolecular schmidt reaction) permits the ready preparation of bicylic lactams with regio-and stereochemical control. Having previously determined some basic characteristics of this reaction, its application to complex natural product targets is proposed. Syntheses of three alkaloids of the stemona class are proposed in this context. A new, related reaction has recently been discovered in these laboratories. The reaction of ketones and aldehydes with hydroxy azides permits the direct synthesis of heterocycles such as oxazolidines, dihydrooxazines, and substituted lactams in a single step. The reaction involves a novel mechanism whereby the addition of azide is rendered intramolecular in the same step in which the carbonyl position undergoes activation by transforming it to an oxonium ion. The overall sequence is the equivalent of an intermolecular schmidt reaction of carbonyls with alkyl azides, a process unknown with simple alkyl azides. The scope, regiochemistry, and stereochemistry of the reaction will be established, with special emphasis given to the development of a recently reported asymmetric variant. The reaction will be used in syntheses of azithromycin analogues (antibiotics), an azamacrolide (insect antifeedant), pseudodistomin B (calmodulin antagonist), and Freidinger lactams (peptidomimetic enzyme inhibitors). Two other total synthesis targets will be pursued due to their novel structures, important biological activities, and as platforms for the invention of additional synthetic methods. They are FR901483, an immunosuppressant recently isolated by the fujisawa Company, and martinelline, a G-protein receptor antagonist.